Synthesis of 17F labeled fluoroalkanes

ABSTRACT

Fluoroalkanes such as fluoromethane labeled with  17 F are produced by contacting  17 F labeled F 2  with alkanes, preferably methane, substituted or unsubstituted alkenes, or substituted or unsubstituted alkynes in the presence of a metal oxide catalyst, preferably a silver oxide catalyst, to produce the  17 F labeled fluoroalkane. The  17 F may be produced by irradiating  20 Ne with protons, preferably having an energy of about 11 MeV and produced by a cyclotron. The  17 F labeled fluoromethane or fluoroalkanes may be produced continuously. A method for determining the location of an  17 F labeled tracer includes generating an  17 F labeled fluoroalkane, administering the  17 F labeled fluoroalkane to a test subject, and scanning the test subject with a radiosensitive detector such as a positron emission tomography scanner.

CROSS REFERENCES TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional ApplicationNo. 60/230,780, filed Sep. 7, 2000, the entire disclosure of which isincorporated herein by reference.

GOVERNMENT RIGHTS

[0002] This invention was made with United States government supportawarded by the following agency: NIMH P50 MH52354. The United States hascertain rights in this invention.

FIELD OF THE INVENTION

[0003] This invention pertains generally to the production of ¹⁷F and tothe synthesis of ¹⁷F labeled fluoromethane and other fluoroalkanes andthe use of such labeled materials in positron emission tomography.

BACKGROUND OF THE INVENTION

[0004] Positron emission tomography (PET) has found wide application asa diagnostic method. Various radioisotopes have been investigated forapplication in PET and other diagnostic imaging methods. One of theseradioisotopes is ¹⁵O ¹⁵O (t½=122 seconds) tracers such as ¹⁵O labeledwater are currently the most commonly used tracers in PET. One advantageof ¹⁵O labeled water as a tracer is that it can be easily and reliablysynthesized. A disadvantage, however, is that it has a relatively lowpermeability surface product such that at high flows, the signal isreduced.

[0005] Eichling et al. Circ. Res. 35, 358-364 (1974); Herscovitch et al.J. Cereb. Blood Flow Metab. 7, 527-542 (1987); Renkin, E. M. Am J.Physiol. 197, 1205-1210 (1959). Additionally, tracers such as ¹⁵Olabeled water are usually administered by injection and are slow toclear test subjects.

[0006] Another radioisotope that has been used is ¹⁸F (t½=110 minutes)in tracers such as ¹⁸F labeled fluoromethane which has been used todetermine regional cerebral blood flow (rBCF). Gatley, et al. Int. J.Appl. Radiat. Isot. 32, 211-214, (1981). Because of the relatively longhalf life of ¹⁸F, tracers labeled with this isotope are ill suited forthe fast repetitions necessary for cerebral activation protocols.

[0007] The short half life of ¹⁷F (Eβ⁺(max)=1.74 MeV; t½≈64 seconds)suggests that this might be a suitable radioisotope for use in PET. Theshort half life presents problems, however, in that tracers labeled withthis isotope must be prepared quickly in order to preserve the maximumamount of ¹⁷F in a labeled compound.

[0008]¹⁷F labeled fluoromethane has been prepared by several routes. Forexample, ¹⁷F labeled fluoromethane has reportedly been produced byHunsdiecker like decomposition of ¹⁷F acetyl hypofluorite and by passageof ¹⁷F labeled F₂ through CH₃HgCl. Mulholland et al. J. Nuc. Med 28,1082, (1987). These methods do not produce ¹⁷F labeled fluoromethane insufficient yield for practical imaging use.

[0009] Therefore, a need exits for an improved method of generating ¹⁷Fand for producing labeled fluoromethane and other fluoroalkanes from it.A need also remains for improved diagnostic methods using ¹⁷F labeledfluoromethane and other fluoroalkanes.

SUMMARY OF THE INVENTION

[0010] The present invention provides ¹⁷F labeled fluoromethane andother ¹⁷F labeled fluoroalkanes, and methods for producing ¹⁷F labeledfluoromethane and other ¹⁷F labeled fluoroalkanes. The invention alsoprovides methods of determining the location of an ¹⁷F labeled tracer.

[0011] A method of generating ¹⁷F labeled fluoroalkanes includescontacting ¹⁷F labeled F₂ with an alkane, preferably methane, asubstituted or unsubstituted alkene, or a substituted or unsubstitutedalkyne in the presence of a metal oxide catalyst to produce the ¹⁷Flabeled fluoroalkane. In more preferred embodiments, the ¹⁷F labeled F₂is contacted with the alkane, the substituted or unsubstituted alkene,or the substituted or unsubstituted alkyne in the presence of the metaloxide catalyst and neon.

[0012] In preferred embodiments, the ¹⁷F is generated by protonirradiation of ²⁰Ne in a target gas stream comprising neon, preferablynatural neon gas.

[0013] In still other embodiments, the target gas stream includes F₂ andneon gas that includes ²⁰Ne whereas in still other preferredembodiments, the target gas stream includes helium, F₂, and neon gasthat includes ²⁰Ne.

[0014] In preferred embodiments, the ²⁰Ne is irradiated with protonshaving an energy of greater than 8 MeV, more preferably with an energyof about 11 MeV. In another preferred embodiment the protons have anenergy of about 16 MeV. The protons used to irradiate ²⁰Ne arepreferably generated by a cyclotron.

[0015] In another embodiment, the ¹⁷F is generated by deuteronirradiation of ¹⁶O in a target gas stream that includes O₂.

[0016] In preferred processes, the target gas stream preferablycomprises less than or about 1.0 percent, more preferably less thanabout 0.7 percent, and most preferably less than about 0.3 percent ofF₂. In still other preferred embodiments the total pressure of thetarget gas ranges from about 100 to about 400 psig or more preferablyranges from about 160 to about 240 psig.

[0017] In other preferred embodiments of producing ¹⁷F labeledfluoromethane, the ¹⁷F labeled F₂ is contacted with methane, and themetal oxide catalyst is silver oxide, preferably at a temperatureranging from about 200° C. to about 600° C. More preferably, the metaloxide is at a temperature ranging from about 400° C. to about 500° C.,and most preferably the metal oxide is at a temperature of about 450° C.

[0018] In other more preferred embodiments of producing ¹⁷F labeledfluoroalkanes, the ¹⁷F labeled F₂ is contacted with the substituted orunsubstituted alkene or the substituted or unsubstituted alkyne and themetal oxide catalyst is silver oxide which is more preferably at atemperature ranging from about 10° C. to about 600° C. or still morepreferably is at a temperature ranging from about 20° C. to about 100°C. Most preferably, the metal oxide catalyst is at a temperature ofabout 25° C. in the process for producing ¹⁷F labeled fluoroalkanes.

[0019] In still other preferred embodiments, the alkene or alkynecontacted with the ¹⁷F labeled F₂ is a haloalkene or haloalkyne, morepreferably a fluorinated alkene or alkyne. Still more preferably, thealkene is a difluoroalkene, yet more preferably 1, 1-difluoroethylenesuch that the ¹⁷F labeled fluoroalkane produced is ¹⁷F labeled 1,1,1,2-tetrafluoroethane where one of the fluorine atoms is an ¹⁷F fluorineatom.

[0020] In still other preferred embodiments, the ¹⁷F labeledfluoroalkane is passed through a scrubber, preferably a soda limescrubber.

[0021] In yet other preferred embodiments of the method of generatingthe ¹⁷F labeled fluoroalkane, the ¹⁷F is continuously generated bycontinuously irradiating the target gas stream with protons and the ¹⁷Flabeled fluoroalkane is continuously produced by continuously contactingthe ¹⁷F labeled F₂ with the alkane, the substituted or unsubstitutedalkene, or the substituted or unsubstituted alkyne, more preferablymethane.

[0022] A method of determining the location of an ¹⁷F labeled tracer isalso provided. The method includes generating the ¹⁷F labeledfluoroalkane according to the invention; administering the ¹⁷F labeledfluoroalkane to a test subject; and collecting scans of the test subjectusing a radiosensitive detector. In preferred such methods, the ¹⁷Flabeled fluoroalkane is administered to the test subject by having thetest subject inhale the ¹⁷F labeled fluoroalkane. In another preferredmethod of determining the location of an ¹⁷F labeled tracer, the ¹⁷Flabeled fluoroalkane is added to a saline solution and the salinesolution is administered to the test subject.

[0023] Preferred radiosensitive detectors for use in determining thelocation of an ¹⁷F labeled tracer such as ¹⁷F labeled fluoromethane andother ¹⁷F labeled fluoroalkanes, are selected from a scintillationdetector, a Geiger counter, a positron emission tomography scanner, asingle photon emission computed tomography scanner, or a solid statedetector. More preferred radiosensitive detectors for use in the methodof determining the location of an ¹⁷F labeled tracer are positronemission tomography scanners or cameras.

[0024] In other more preferred embodiments of producing ¹⁷F labeledfluoroalkanes, the ¹⁷F labeled F₂ is contacted with the substituted orunsubstituted alkene or the substituted or unsubstituted alkyne and themetal oxide catalyst is silver oxide which is more preferably at atemperature ranging from about 10° C. to about 600° C. or still morepreferably is at a temperature ranging from about 20° C. to about 100°C. Most preferably, the metal oxide catalyst is at a temperature ofabout 25° C. in the process for producing ¹⁷F labeled fluoroalkanes.

[0025] In still other preferred embodiments, the alkene or alkynecontacted with the ¹⁷F labeled F₂ is a haloalkene or haloalkyne, morepreferably a fluorinated alkene or alkyne. Still more preferably, thealkene is a difluoroalkene, yet more preferably 1,1 -difluoroethylenesuch that the ¹⁷F labeled fluoroalkane produced is ¹⁷F labeled1,1,1,2-tetrafluoroethane where one of the fluorine atoms is an ¹⁷Ffluorine atom.

[0026] The invention also provides the ¹⁷F labeled fluoromethane andfluoroalkanes produced by the processes of the invention.

[0027]¹⁷F labeled organic compounds are provided and include ¹⁷F labeledfluoromethane and an ¹⁷F labeled alkane having more than 2 carbon atoms.In more preferred ¹⁷F labeled organic compounds, the alkane comprises atleast two fluorine atoms and at least one of the fluorine atoms is an¹⁷F. In still other more preferred ¹⁷F labeled organic compounds, the¹⁷F labeled alkane is 1,1,1,2-tetrafluoroethane where at least one ofthe F atoms is an ¹⁷F fluorine atom.

[0028] The invention still further provides gaseous compositions thatinclude ¹⁷F labeled fluoromethane that has an equilibrium activity ofgreater than or about 20 mCi. In some preferred embodiments, theequilibrium activity level is greater than or about 40 mCi whereas instill other preferred embodiments, the equilibrium activity level isgreater than or about 70 mCi.

[0029] Further objects, features and advantages of the invention will beapparent from the following detailed description when taken inconjunction with the accompanying drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0030] In the drawings like numerals represent like elements.

[0031]FIG. 1 is a schematic diagram illustrating various parts of anapparatus used for the continuous production of ¹⁷F labeledfluoromethane and other ¹⁷F labeled fluoroalkanes.

[0032]FIG. 2 is a diagram of a production target in which ¹⁷F labeled F₂is produced.

[0033]FIG. 3 is a graph showing the decay of ¹⁷F as a function of timeand the decay of the small amount of ¹⁸F produced as the onlyradionuclidic impurity.

[0034]FIG. 4 is a graph comparing the thick target yield for²⁰Ne(p,α)¹⁷F calculated from published total cross section data (GruhleW., Kober B., Nuclear Physics, A286, 1, 523-530 (1977)) and the measuredyield using a CTI-RDS-112 cyclotron 11 MeV proton beam.

[0035]FIG. 5 is a gas chromatograph showing the radiochemical purity of¹⁷F labeled fluoromethane where the large peak represents ¹⁷F labeledfluoromethane and the small peak represents ¹⁷F labeled CF₄ from thetarget as a radiochemical impurity.

[0036]FIG. 6 is a graph showing the yield of ¹⁷F labeled F₂ as measuredin mCi/μA versus the carrier F₂ flow rate in μmol/minute.

[0037]FIG. 7 is a series of brain flow images obtained from a testsubject after steady state inhalation of 40 mCi of ¹⁷F labeledfluoromethane by the test subject. The test subject was a rhesus monkeyand the instrument was an ECAT 944 PET scanner.

DETAILED DESCRIPTION OF THE INVENTION

[0038] Generally, the invention provides ¹⁷F labeled fluoromethane andother ¹⁷F labeled fluoroalkanes, methods for producing ¹⁷F labeledfluoromethane and other ¹⁷F labeled fluoroalkanes, and methods ofdetermining the location of a ¹⁷F labeled tracer such as with a positronemission tomography scanner.

[0039] All ranges recited herein include all combinations andsubcombinations included within that range's limits. Therefore, atemperature range of from about 200° C. to about 600° C. includes rangesof from 200° C. to 600° C., of from 300° C. to 600° C., of from 250° C.to 500° C., of from 225° C. to 425° C., etc.

[0040] Positron emitting ¹⁷F (Eβ⁺(max)=1.74 MeV; t½≈64 seconds) has anideal half life for probing such diverse processes as gray mattercerebral activity or gas-phase reactions on an industrial scale. Becauseof the very short half life of ¹⁷F, tracers labeled with this isotopesuch as ¹⁷F labeled fluoromethane provide very short half life cerebralblood flow agents that have important application in PET studies ofseizure and other transient brain phenomena. The shorter half life of¹⁷F with respect to ¹⁵O permits repeat images to be obtained twice asfast with ¹⁷F labeled tracers as compared to ¹⁵O labeled tracers such aswater which is presently in wide use as a tracer as described above. Theability to scan twice as fast using ¹⁷F labeled tracers allows more datato be collected in the same amount of time and should allow more testsubjects to be evaluated using instruments that are currently in highdemand. Additionally, ¹⁷F labeled tracers show improved signal to noiselevel ratios over ¹⁵O labeled tracers providing increased sensitivity.¹⁵O tracers such as ¹⁵O labeled water are usually administered in amanner that is more invasive than are tracers such as ¹⁷F labeledfluoromethane. For example, ¹⁵O labeled tracers are usually administeredby injection and arterial measurements are then made from an arterialcannulation. On the other hand, ¹⁷F labeled tracers such asfluoromethane may be administered by having a test subject inhale thetracer, and arterial measurements can be made from exhalations.Furthermore, tracers such as ¹⁷F labeled fluoromethane are rapidlycleared by exhalation and the biological half life is quite short.

[0041] Two nuclear reactions may be used to generate ¹⁷F in practicalyields for use in the present invention. First, and preferably, ¹⁷F maybe produced by the irradiation of ²⁰Ne in a nuclear reaction that may bewritten as ²⁰Ne(p,α)¹⁷F with A(EOSB) of 14 mCi/μA leaving the targetwith an E_(p) equal to 11 MeV where EOSB stands for end of saturationbombardment. ¹⁷F may also be produced by the deuteron irradiation of ¹⁶Oin natural or other O₂ in a process that may be written ¹⁶O(d,n) ¹⁷Fwith A(EOSB) of 125 mCi/μA and an E_(d) value of 11 MeV. Addition ofsmall amounts of F₂ to either target gas has been found to bring the ¹⁷Factivity quantitatively out of the aluminum target. The production of¹⁷F by proton irradiation of ²⁰Ne has several advantages over theproduction by deuteron irradiation of ¹⁶O. First, the ¹⁷F is produced inan inert gas for improved fast radiochemistry. Second, production of ¹⁷Fby proton irradiation of ²⁰Ne is readily implementable using low energyproton cyclotrons. The ²⁰Ne is generally supplied as a component ofnatural neon which refers to neon gas having various isotopes and whichis the type of neon commonly available and sold in gas cylinders.Similarly, natural O₂ refers to oxygen that is readily available andsold in standard gas cylinders and is found as a component in theearth's atmosphere.

[0042] Because of the relatively short half life of ¹⁷F, tracers labeledwith this radioisotope must be prepared quickly to maintain optimallevels of ¹⁷F in the tracer. ¹⁷F labeled fluoromethane, [¹⁷F]CH₃F, maybe conveniently and quickly generated by contacting methane, methylbromide, methyl chloride, or methyl iodide with ¹⁷F labeled F₂ in thepresence of a metal oxide catalyst, preferably a silver oxide catalyst.More preferably, ¹⁷F labeled fluoroalkanes are prepared by contacting¹⁷F labeled F₂ with methane or other alkanes in the presence of a metaloxide catalyst where the metal oxide is at a temperature ranging fromabout 200° C. to about 600° C. or still more preferably at a temperatureof from about 400° C. to about 500° C. or yet more preferably at atemperature of about 450° C. Alkanes that may be used to prepare ¹⁷Flabeled fluoroalkanes include linear, branched chain, and cyclicalkanes. Examples of such alkanes other than methane include, but arenot limited to, ethane, propane, cyclopropane, butane, cyclobutane,methylcyclopropane, 2-methylpropane, 2-methylbutane, 2,3-dimethylbutane,methylcyclobutane, pentane, cyclopentane, hexane, methylcyclopentane,cyclohexane, and mixtures thereof.

[0043] Other ¹⁷F labeled fluoroalkanes may be generated by contacting¹⁷F labeled F₂ with a substituted or unsubstituted alkene or alkyne witha metal oxide catalyst, preferably a silver oxide catalyst. In suchprocesses, the metal oxide catalyst is preferably at a temperatureranging from about 10° C. to about 600° C. or more preferably is at atemperature of from about 20° C. to about 100° C. Most preferably inprocesses using alkenes or alkynes, the metal oxide catalyst is at atemperature of about 25° C. In particular, the preparation of a ¹⁷Flabeled 1,1,1,2-tetrafluoroalkane may be accomplished by contacting ¹⁷Flabeled F₂ with 1,1-difluoroethylene in the presence of the metal oxidecatalyst. The ¹⁷F labeled fluoromethane and other fluoroalkanes may beused as tracer compounds in positron emission tomography and in thestudy of industrial gases such as 1,1,1,2-tetrafluoroethane-acommercially important refrigerant. The process for generating ¹⁷Flabeled F₂, ¹⁷F labeled fluoromethane, and other ¹⁷F labeledfluoroalkanes is better explained with reference to FIG. 1.

[0044]FIG. 1 is a schematic diagram of an apparatus 10 that may be usedin the continuous production of ¹⁷F labeled fluoromethane and other ¹⁷Flabeled fluoroalkanes. As shown in FIG. 1, the target gas, preferably²⁰Ne in natural neon gas, is supplied to the system from a target gascylinder 20 with a metering valve 30 through line 40 whereas F₂ issupplied to the system from a gas cylinder 50 with a metering valve 60through line 70. The F₂ is most preferably supplied as a component of agas mixture so that it is in a diluted rather than in a pure form. Thus,gas cylinder 50 generally supplies a mixture of gases to the systemwhere less than about 5 percent of the gas mixture is F₂. In onepreferred embodiment, the remainder of gas in cylinder 50 is an inertgas such as helium. In another preferred embodiment the remainder of gasin cylinder 50 is neon. The target gas from cylinder 20 is mixed withthe gas mixture from cylinder 50 forming a target gas stream which flowsthrough line 70 to target 80 shown in greater detail in FIG. 2.

[0045] One skilled in the art will recognize that it is not necessarythat the F₂ and neon be supplied to the target 80 from separate sources.For example, in a highly preferred embodiment, a mixture of neon and F₂is used to supply the target gas such that the target gas in cylinder 20comprises F2 and a species to be irradiated, preferably ²⁰Ne in naturalneon gas. Thus, in a highly preferred process, cylinder 20 comprises F₂and natural neon which includes ²⁰Ne as one of its component isotopes ofNe. No helium is required or necessary in such a process although it maycertainly be present without deleterious effect on the process.

[0046] The target gas stream preferably includes ²⁰Ne and F₂ and morepreferably includes ²⁰Ne, F₂, and helium in one embodiment. Mostpreferably, as described above, the target gas stream comprises F₂ andnatural neon gas that includes ²⁰Ne among other isotopes of Ne. Thetarget gas stream generally is less than about 3.0 percent F₂. In mostprocesses, however, the target gas stream is less than 1.0 percent F₂,is more preferably less than about 0.7 percent F₂, and is still morepreferably less than about 0.3 percent F₂ although those skilled in theart will recognize that various levels of F₂ may be used in the processof the invention. The percentage of neon and helium in a target gasstream may vary considerably. Generally, when helium is present in thetarget gas stream, the percentage of neon in the target gas stream isgreater than 70 percent. More preferably in helium-containing gasstreams, however, the percentage of neon in the target gas stream isgreater than about 85 percent. Still more preferably inhelium-containing target streams, the percentage of neon in the targetgas stream is greater than or about 87 percent with helium and F₂ makingup the remainder of such target gas streams.

[0047] In preferred processes which do not use helium, but ratherconsist essentially of neon and F₂, the percentage of neon in the targetgas stream is greater than 97 percent. In more preferred such processes,the percentage of neon in the target gas stream is greater than about 98percent. In still more preferred such processes, the percentage of neonin the target gas stream is greater than about 99 percent, and stillmore preferably is greater than about 99.5 percent.

[0048] The pressure of the target gas stream preferably ranges fromabout 100 to about 400 psig although those skilled in the art willrecognize that the target gas stream may be at pressures outside thisrange. More preferably, the total pressure of the target gas streamranges from about 120 to about 300 psig, and still more preferablyranges from about 160 to about 240 psig. The flow rate of the target gasstream into target 80 may vary considerably, but is typically maintainedat a range of from about 100 to about 300 mL/minute. More preferably,the flow rate is maintained at from about 130 to about 220 mL/minute.

[0049] In the target 80, the target gas mixture is irradiated with astream of protons 90 having an energy of greater than 8 MeV, preferablyhaving an energy of about 11 MeV and supplied by a cyclotron such as aCTI-RDS-112cyclotron (not shown) or having an energy of about 16 MeV andsupplied by a cyclotron such as a PET Trace cyclotron available fromGeneral Electric. Irradiation of ²⁰Ne with the protons produces ¹⁷F andgives rise to the ¹⁷F labeled F₂ used to produce ¹⁷F labeledfluoromethane and other ¹⁷F labeled fluoroalkanes.

[0050] After leaving target 80, a metering valve 100 is used to regulatethe flow of the ¹⁷F labeled F₂ containing gas stream which moves throughline 110 to a column 120 containing a metal oxide catalyst. Metal oxidecatalysts for use in the process include, but are not limited to copperoxide, nickel oxide, and silver oxide with silver oxide being a highlypreferred metal oxide catalyst. Prior to entering column 120, a reactantgas supplied from cylinder 130 and regulated with metering valve 140 isadded to the gas stream containing the ¹⁷F labeled F₂ through line 150.Because the gas stream contains neon, the reactant gas preferablycontacts the ¹⁷F labeled F₂ in the presence of the metal oxide catalystand neon. For producing ¹⁷F labeled fluoromethane, the reactant gas incylinder 130 is preferably methane, methyl bromide, methyl chloride, ormethyl iodide, but is most preferably methane. For producing other ¹⁷Flabeled fluoroalkanes, the reactant gas is preferably a substituted orunsubstituted alkene or alkyne such as, but not limited to substitutedor unsubstituted ethylene, propylene, 1-butene, 2-butene, pentenes,hexenes, cyclopentene, cyclohexene, acetylene, 1-propyne, 1-butyne,2-butyne, pentynes, or hexynes. The alkenes or alkynes are preferablyhaloalkenes or haloalkynes and are more preferably fluoroalkenes oralkynes such as difluoroalkenes. An example of a particularly preferredsubstituted alkene is 1,1-difluoroethylene which reacts with ¹⁷F labeledF₂ to produce ¹⁷F labeled 1,1,1,2-tetrafluoroethane.

[0051] As described above, for the production of fluoromethane, themetal oxide catalyst is preferably at a temperature ranging from about200° C. to about 600° C., more preferably ranging from about 400° C. toabout 500° C., and most preferably is at a temperature of about 450° C.When the reactant gas is a substituted or unsubstituted alkene oralkyne, the metal oxide is preferably at a temperature ranging fromabout 10° C. to about 600° C., but is more preferably at a temperatureranging from about 20° C. to about 100° C. Most preferably, when thereactant gas is a substituted or unsubstituted alkene or alkyne, thetemperature of the metal oxide catalyst is about 25° C. or roomtemperature. The column containing the metal oxide catalyst may beheated, if desired, using any conventional means known to those skilledin the art such as heating tape or coils.

[0052] The reactant gas from cylinder 130 may be added to the gas streamcontaining the ¹⁷F labeled F₂ at various flow rates which will berecognized by those skilled in the art. However preferred flow ratesgenerally range from about 1 to about 10 mL/minute. A particularlypreferred flow rate for the reactant gas is a rate of about 3 mL/minute.The reactant gas may be added to the system in a pure or diluted form.For example, methane may be added in a pure form or as a mixture with aninert gas such as helium or neon.

[0053] As described above, the ¹⁷F labeled F₂ preferably contacts thereactant gas in the presence of the metal oxide catalyst while in column120.

[0054] After passing through column 120, the product stream containingthe ¹⁷F labeled fluoromethane or other fluoroalkane passes through line160. Line 160 preferably passes through a scrubber 170 such as a sodalime scrubber or trap to remove F₂ and HF from the ¹⁷F labeledfluoromethane or other ¹⁷F labeled fluoroalkane. Tests with KI indicatorstrips showed that no detectable F₂ remained in the stream following thesoda lime scrubber. Other separation devices such as filter 180, can beused to remove mass contaminants to undetectable levels. One suchpreferred type of filter is a Waters Sep-Pak Plus C18 cartridge filter.

[0055] Typical production using the procedure and apparatus set forthabove with protons having an energy of about 11 MeV at a 10-15 μA beamprovided 100 to 150 mCi of ¹⁷F labeled F₂, and 35 to 50 mCi of ¹⁷Ffluoromethane when methane was used as the reactant gas. The process maybe used to prepare gaseous compositions that include ¹⁷F labeledfluoromethane and have an equilibrium activity of greater than or about20 mCi, of greater than or about 40 mCi, or of greater than or about 70mCi.

[0056] Such gaseous compositions generally will also contain neon ormixtures of neon and helium.

[0057] Using the apparatus described above, ¹⁷F labeled fluoromethanewas produced in yields approaching the theoretical maximum of 50 percentby the addition of methane at approximately 2 percent to a target streamcontaining neon, helium and 0.5 percent F₂ after the target stream hadbeen irradiated with protons and the resulting mixture containingmethane had been passed through a column of powdered silver oxide at450° C. Gas chromatography (Porpak Q column; He carrier gas; thermalconductivity detector, electrochemical detector, and positroncoincidence radiation detector) indicated that the radiochemical purityof [¹⁷F]CH₃F was greater than 90 percent with less than a 100 ppm[¹⁸F]CH₃F radionuclidic contaminant. With approximately 10 μA of 11 MeVprotons on target, continuous gas flow saturated the ballast reservoirat 44 mCi at a PET scanner located 20 meters away. Anesthetized primatesdrawing from this continuously replenished supply of ¹⁷F labeledfluoromethane exhibited a cerebral counting rate that rapidly reached aplateau of 100 kcps (7 slices, 52 mm axial field of view, 2D, CTI 933/04PET camera). This permitted megacount flow images in a minute. The endexpiratory concentration of CH₃ ¹⁷F was monitored by a flow-through betadetector, and provided the arterial concentration sufficient forquantifying regional cerebral blood flow.

[0058] Using the apparatus described above, F labeled1,1,1,2-tetrafluoroethane was produced almost quantitatively by reactionof ¹⁷F labeled F₂ with 1,1-difluoroethylene in the gas-jet reaction oversilver oxide at room temperature. The radiochemical purity was found tobe in excess of 80 percent as determined by gas chromatography.

[0059] The neon gas used in the apparatus described above was CP gradeand obtained from Air Products. The F₂ gas was obtained as a gas mixtureof 5 percent F₂ in helium from Air Products. Monel brand and stainlesssteel Swagelok brand fittings were used. Valves used in the apparatusincluded Nupro brand (M- or SS- BG or BK valves, Whitey brand SS-41S1and 41XS1 valves, and Swagelok brand SS-S1 valves. The tubing of thevarious lines was typically {fraction (1/16)} inch stainless steel orpolytetrafluoroethylene (PTFE). The target used was that shown in FIG.2.

[0060] As described above, FIG. 2 shows one target 80 that may be usedto generate ¹⁷F labeled F₂ from ²⁰Ne in a target gas stream. The target80 includes an aluminum housing 190 and an aluminum end flange 200secured to housing 190 with screws 210. Aluminum end flange 200 definesan inlet 220 through which the target gas stream is introduced into theinterior of housing 190. Inlet fitting 230 is used to connect target 80to a feed gas supplied through line 70. On the other end of target 80 isthe double foil cooling and target mount assembly 240 which securestarget 80. The target 80 is cooled with a water cooling line 250. Viton®brand O-rings 260 are used to seal target 80. In operation, protonsgenerated by the cyclotron (not shown) enter the interior of the housing190 of target 80 through Havar foil 270 of about 0.0012 inch thickness.The protons irradiate the ²⁰Ne in the interior of target 80 and convert²⁰Ne into ¹⁷F which subsequently forms ¹⁷F labeled F₂. The gaseousproduct leaves target 80 by passing through gas outlet 255 which has adiameter of about 0.040 inches. The gaseous product then continues to astainless steel gas exit tube 265 held onto target 80 by a flange 270and O-rings 280. An outlet fitting 290 connects gas exit tube 265 toline 110 which directs the ¹⁷F labeled F₂ containing stream to column120. A metering valve may be used to control the flow of gas from target80 into line 110.

[0061] One skilled in the art will recognize that other flow throughtarget geometries may be used to generate the ¹⁷F in the process of theinvention. Thus, the choice of a target such as that shown in FIG. 2 isnot critical to the processes for preparing ¹⁷F labeled F₂, ¹⁷F labeledfluoromethane, or other fluoroalkanes.

[0062] Additionally, one skilled in the art will recognize that ¹⁷Flabeled F₂ may be produced by deuteron irradiation of ¹⁶O as describedabove. In such a system, neon is not necessary, but the remainder of thesystem is similar to that described in FIG. 1. In a system using ¹⁶O anddeuteron bombardment to produce ¹⁷F labeled F₂, a mixture of F₂ and O₂,preferably natural O₂ gas, is supplied to a target and then irradiatedwith deuterons having an energy of greater than 1 MeV. In such a system,the gas stream leaving the target would include ¹⁷F labeled F₂ and O₂which would then proceed to column 120 containing the metal oxidecatalyst.

[0063]FIG. 3 is a graph showing the decay of ¹⁷F as a function of time.

[0064] The decay analysis of ¹⁷F labeled F₂ was performed after 5minutes and 15 μA irradiation under standard flow conditions. Thecalculated ¹⁸F/¹⁷F number ratio in the gas stream was determined to be3×10⁻⁵, resulting in approximately 0.2 mCi total ¹⁸F buildup in a 60minute experiment under these conditions, compared to the equilibrium150-175 mCi ¹⁷F.

[0065]FIG. 4 is a graph comparing the thick target yield for²⁰Ne(p,α)¹⁷F calculated from published total cross section data (GruhleW., Kober B., Nuclear Physics, A286, 1, 523-530 (1977)) and the measuredyield using a CTI-RDS-112 cyclotron 11 MeV proton beam. The measuredyield of about 20 mCi/μA is corrected for transport decay (12 seconds),neon fraction in target gas (87%), and natural ²⁰Ne fraction (90.5%)

[0066]FIG. 5 is a gas chromatograph (Porpak Q column; He carrier gas;thermal conductivity detector, electrochemical detector, and positroncoincidence radiation detector) showing the radiochemical purity of ¹⁷Flabeled fluoromethane produced by the present invention. Theradiochemical purity of the ¹⁷F labeled fluoromethane was determined tobe 91 percent with only ¹⁷F labeled CF₄ from the target as aradiochemical impurity. Notably, when used as a tracer, CF₄ stays out ofthe blood when inhaled. Thus, the presence of CF₄ only impacts thedosimetry to the lungs and trachea.

[0067]FIG. 6 is a graph of the yield of ¹⁷F labeled F₂ as measured inmCi/μA as a function of carrier F₂ flow as measured in μmol/minute at afixed Ne pressure. As shown in the graph, a maximum yield of about 15mCi/μA occurs at a F₂ flow of about 75 μmol/minute. The decrease inyield at higher concentrations of F₂ is attributed to dilution of the²⁰Ne due to the added helium in the helium/F₂ gas mixture.

[0068] The location of ¹⁷F labeled tracers such as ¹⁷F labeledfluoromethane and other ¹⁷F labeled fluoroalkanes can be determinedusing a simple method. Typically, the ¹⁷F labeled tracer is firstgenerated using the processes of the present invention. The tracer isthen administered to a test subject such as a human, animal, plant,process plant, or a chemical reaction. After the tracer has beenadministered to the test subject, the test subject is scanned using aradiosensitive detector. Examples of suitable radiosensitive detectorsinclude, but are not limited to, scintillation detectors, Geigercounters, positron emission tomography scanners, single photon emissioncomputed tomography scanners, and solid state detectors such as, but notlimited to, PIN diodes, silicon-based detectors, and germanium-baseddetectors. A more preferred radiosensitive detector for use in themethod of determining the location of an ¹⁷F labeled tracer is apositron emission tomography scanner or camera which may be used toperform positron emission tomography as described below as an example ofa type of method of determining the location of an ¹⁷F labeled tracer.

[0069] Positron emission tomography can be readily accomplished usingthe ¹⁷F labeled fluoromethane and other ¹⁷F labeled fluoroalkanesproduced by the process of the invention as tracers. Typically, the ¹⁷Flabeled compound is administered to a test subject and then scans arecollected on the test subject using a positron emission tomographyscanner. ¹⁷F labeled fluoromethane or other ¹⁷F labeled fluoroalkanesare most preferably administered to human and animal test subjects byhaving the test subject inhale a gas mixture containing the ¹⁷F labeledmaterial. Alternatively, the ¹⁷F labeled compound may be added to asaline solution and then administered to an animal or human test subjectsuch as by intravenous injection. A condenser such as a Waters Sep-PakPlus C18 cartridge filter may be used in conjunction with ethanol/dryice to trap fluoroalkanes such as fluoromethane. The Waters Sep-Pak PlusC18 cartridge filter may then be rinsed with saline to produce thesaline solution for administration.

[0070]FIG. 7 shows brain flow images obtained with an ECAT 933 PETscanner using ¹⁷F labeled fluoromethane as a tracer. The test subjectwas a rhesus monkey. The ¹⁷F labeled fluoromethane was administered byhaving the rhesus monkey inhale the tracer at a steady state level of 40mCi.

[0071] It is understood that the invention is not limited to theembodiments set forth herein for illustration, but embraces all suchforms thereof as come within the scope of the following claims.

What is claimed is:
 1. A method of generating a ¹⁷F labeledfluoroalkane, comprising: contacting ¹⁷F labeled F₂ with an alkane, asubstituted or unsubstituted alkene, or a substituted or unsubstitutedalkyne in the presence of a metal oxide catalyst to produce the ¹⁷Flabeled fluoroalkane.
 2. The method of generating a ¹⁷F labeledfluoroalkane according to claim 1, wherein the ¹⁷F labeled F₂ iscontacted with methane, the metal oxide catalyst is at a temperatureabove room temperature, and the ¹⁷F labeled fluoroalkane is ¹⁷F labeledfluoromethane.
 3. The method of generating a ¹⁷F labeled fluoroalkaneaccording to claim 1, wherein the ¹⁷F labeled F₂ is contacted withmethane and ¹⁷F labeled fluoromethane is produced.
 4. The method ofgenerating a ¹⁷F labeled fluoroalkane according to claim 1, furthercomprising irradiating ²⁰Ne in a target gas stream comprising neon withprotons to produce the ¹⁷F.
 5. The method of generating a ¹⁷F labeledfluoroalkane according to claim 4, wherein the neon in the target gasstream comprises natural neon gas.
 6. The method of generating a ¹⁷Flabeled fluoroalkane according to claim 1, further comprisingirradiating ¹⁶O in a target gas stream comprising O₂ with deuterons toproduce the ¹⁷F.
 7. The method of generating a ¹⁷F labeled fluoroalkaneaccording to claim 1, wherein the ¹⁷F labeled F2 is contacted with thealkane, the substituted or unsubstituted alkene, or the substituted orunsubstituted alkyne in the presence of the metal oxide catalyst andneon.
 8. The method of generating a ¹⁷F labeled fluoroalkane accordingto claim 1, wherein the metal oxide catalyst is silver oxide.
 9. Themethod of generating a ¹⁷F labeled fluoroalkane according to claim 8,wherein the ¹⁷F labeled F₂ is contacted with methane, and the methodfurther comprises maintaining the metal oxide catalyst at a temperatureranging from about 200° C. to about 600° C.
 10. The method of generatinga ¹⁷F labeled fluoroalkane according to claim 9, wherein the metal oxidecatalyst is maintained at a temperature ranging from about 400° C. toabout 500° C.
 11. The method of generating a ¹⁷F labeled fluoroalkaneaccording to claim 10, wherein the metal oxide catalyst is maintained ata temperature of about 450° C.
 12. The method of generating a ¹⁷Flabeled fluoroalkane according to claim 8, wherein the ¹⁷F labeled F₂ iscontacted with the substituted or unsubstituted alkene or thesubstituted or unsubstituted alkyne, and the method further comprisesmaintaining the metal oxide catalyst at a temperature ranging from about10° C. to about 600° C.
 13. The method of generating a ¹⁷F labeledfluoroalkane according to claim 12, wherein the metal oxide catalyst ismaintained at a temperature ranging from about 20° C. to about 100° C.14. The method of generating a ¹⁷F labeled fluoroalkane according toclaim 13, wherein the metal oxide catalyst is maintained at atemperature of about 25° C.
 15. The method of generating a ¹⁷F labeledfluoroalkane according to claim 1, wherein the ¹⁷F labeled F₂ iscontacted with the substituted or unsubstituted alkene or thesubstituted or unsubstituted alkyne.
 16. The method of generating a ¹⁷Flabeled fluoroalkane according to claim 1, wherein the ¹⁷F labeled F₂ iscontacted with a haloalkene or a haloalkyne.
 17. The method ofgenerating a ¹⁷F labeled fluoroalkane according to claim 16, wherein thehaloalkene or the haloalkyne is a fluorinated alkene or alkyne.
 18. Themethod of generating a ¹⁷F labeled fluoroalkane according to claim 17,wherein the fluorinated alkene is a difluoroalkene.
 19. The method ofgenerating a ¹⁷F labeled fluoroalkane according to claim 18, wherein thefluorinated alkene is 1,1-difluoroethylene and the ¹⁷F labeledfluoroalkane is ¹⁷F labeled 1,1,1,2-tetrafluoroethane.
 20. The method ofgenerating a ¹⁷F labeled fluoroalkane according to claim 4, wherein thetarget gas stream comprises F₂ and neon comprising ²⁰Ne.
 21. The methodof generating a ¹⁷F labeled fluoroalkane according to claim 20, whereinthe ²⁰Ne is irradiated with protons having an energy of greater than 8MeV.
 22. The method of generating a ¹⁷F labeled fluoroalkane accordingto claim 21, wherein the ²⁰Ne is irradiated with protons having anenergy of about 11 MeV.
 23. The method of generating a ¹⁷F labeledfluoroalkane according to claim 21, wherein the ²⁰Ne is irradiated withprotons having an energy of about 16 MeV.
 24. The method of generating a¹⁷F labeled fluoroalkane according to claim 21, further comprisingproducing the protons with a cyclotron.
 25. The method of generating a¹⁷F labeled fluoroalkane according to claim 20, wherein the target gasstream further comprises helium.
 26. The method of generating a ¹⁷Flabeled fluoroalkane according to claim 20, wherein the target gasstream comprises less than about 1.0 percent F₂.
 27. The method ofgenerating a ¹⁷F labeled fluoroalkane according to claim 26, wherein thetarget gas stream comprises less than about 0.7 percent F₂.
 28. Themethod of generating a ¹⁷F labeled fluoroalkane according to claim 27,wherein the target gas stream comprises less than about 0.3 percent F₂.29. The method of generating a ¹⁷F labeled fluoroalkane according toclaim 4, wherein the target gas stream is at a total pressure rangingfrom about 100 to about 400 psig.
 30. The method of generating a ¹⁷Flabeled fluoroalkane according to claim 29, wherein the target gas is ata total pressure of from about 160 to about 240 psig.
 31. The method ofgenerating a ¹⁷F labeled fluoroalkane according to claim 1, furthercomprising passing the ¹⁷F labeled fluoroalkane through a scrubber. 32.The method of generating a ¹⁷F labeled fluoroalkane according to claim31, wherein the scrubber is a soda lime scrubber.
 33. The method ofgenerating a ¹⁷F labeled fluoroalkane according to claim 4, wherein the¹⁷F is continuously generated by continuously irradiating the target gasstream with protons and the ¹⁷F labeled fluoroalkane is continuouslyproduced by continuously contacting the ¹⁷F labeled F₂ with the alkane,the substituted or unsubstituted alkene, or the substituted orunsubstituted alkyne.
 34. The method of generating a ¹⁷F labeledfluoroalkane according to claim 1, wherein the ¹⁷F labeled F₂ iscontacted with the alkane, and the alkane is a linear, branched chain,or cyclic alkane selected from the group consisting of ethane, propane,cyclopropane, butane, cyclobutane, methylcyclopropane, 2-methylpropane,2-methylbutane, 2,3-dimethylbutane, methylcyclobutane, pentane,cyclopentane, hexane, methylcyclopentane, and cyclohexane.
 35. A methodof determining the location of a ¹⁷F labeled tracer, comprising: (a)generating the 1 ⁷F labeled fluoroalkane according to the method ofclaim 1; (b) administering the ¹⁷F labeled fluoroalkane to a testsubject; and (c) collecting scans of the test subject using aradiosensitive detector.
 36. The method of determining the location of a¹⁷F labeled tracer according to claim 35, wherein the ¹⁷F labeledfluoroalkane is administered to the test subject by having the testsubject inhale the ¹⁷F labeled fluoroalkane.
 37. The method ofdetermining the location of a ¹⁷F labeled tracer according to claim 35,further comprising adding the ¹⁷F labeled fluoroalkane to a salinesolution and administering the saline solution to the test subject. 38.The method of determining the location of a ¹⁷F labeled tracer accordingto claim 35, wherein the radiosensitive detector is selected from thegroup consisting of a scintillation detector, a Geiger counter, apositron emission tomography scanner, a single photon emission computedtomography scanner, and a solid state detector.
 39. The method ofdetermining the location of a ¹⁷F labeled tracer according to claim 38,wherein the radiosensitive detector is a positron emission tomographyscanner.
 40. The method of determining the location of a ¹⁷F labeledtracer according to claim 35, wherein the ¹⁷F labeled fluoroalkane is¹⁷F labeled fluoromethane.
 41. The ¹⁷F labeled fluoromethane produced bythe method according to claim
 3. 42. The ¹⁷F labeled fluoroalkaneproduced by the method according to claim
 15. 43. An ¹⁷F labeled organiccompound, comprising an ¹⁷F labeled alkane having 2 or more carbonatoms.
 44. The ¹⁷F labeled organic compound according to claim 43,wherein the alkane comprises at least two fluorine atoms and at leastone of the fluorine atoms is an ¹⁷F.
 45. The ¹⁷F labeled organiccompound according to claim 44, wherein the ¹⁷F labeled alkane comprises1,1,1,2-tetrafluoroethane wherein at least one of the F atoms is an ¹⁷F.46. A gaseous composition, comprising ¹⁷F labeled fluoromethane andhaving an equilibrium activity of greater than or about 20 mCi.
 47. Thegaseous composition according to claim 46, wherein the equilibriumactivity is greater than or about 40 mCi.
 48. The gaseous compositionaccording to claim 46, wherein the equilibrium activity is greater thanor about 70 mCi.
 49. The gaseous composition according to claim 46,further comprising neon.